Papillary Muscle Delayed Hyperenhancement

Background Papillary muscle–delayed hyperenhancement (papHE) at cardiac magnetic resonance indicates fibrotic or infiltrative processes. Contrary to myocardial HE, the prevalence and prognostic implications of papHE in patients with nonischemic dilated cardiomyopathy are unclear. Objectives The purpose of this study was to determine the prevalence of papHE and describe its association with adverse clinical outcomes. Methods This prospective cohort study included 528 patients who underwent late gadolinium enhancement cardiac magnetic resonance. The primary outcomes were all-cause mortality, sudden cardiac death, life-threatening arrhythmia, and hospitalization for heart failure. Patients were allocated into 4 categories: the first without papHE and without myocardial HE, the second with papHE, the third with myocardial HE, and the fourth with papHE and myocardial HE. The hazards of the primary outcomes for each category were compared using multivariable Cox regression. Results papHE was present in 131 patients (25%). The median follow-up duration was 6.1 years (IQR: 3.7-9.7 years). Isolated papHE and isolated myocardial HE were not significantly associated with any of the prespecified outcomes. Patients who had both myocardial HE and papHE were at an increased risk of all-cause mortality (HR: 2.33, 95% CI: 1.26-4.30), sudden cardiac death (HR: 3.77, 95% CI: 1.59-8.94), life-threatening arrhythmia (HR: 3.94, 95% CI: 1.34-11.58), and hospitalization for heart failure (HR: 2.97, 95% CI: 1.30-6.80). Conclusions The combined presence of myocardial and papHE was independently associated with adverse outcomes. Future studies should investigate if the incorporation of papHE and myocardial HE may improve clinical decision-making strategies to select dilated cardiomyopathy patients who would benefit the most from ICD implantation.

N onischemic dilated cardiomyopa- thy (DCM) is defined as left ventricle (LV) dilation and systolic dysfunction, in the absence of significant coronary artery disease or pathological loading conditions such as valvulopathies, congenital heart disease, or hypertension. 1Patients with DCM are at an increased risk of cardiovascular mortality (6.6% percent at 3.8 years), heart failure hospitalizations (HFH), and ventricular arrhythmias. 2plantable cardioverter-defibrillators (ICD) can be used to mitigate the risk of ventricular arrhythmias and consequent sudden cardiac death (SCD). 35][6] Secondly, ICD implantation in DCM patients for primary prevention does not significantly reduce all-cause mortality. 6Therefore, additional selection criteria for ICD implantation are needed to select patients who would benefit the most from ICD implantation, 3 in an effort to further reduce SCD rates without unnecessary treatment.One of the proposed criteria is the presence of subendocardial, midwall, and epicardial delayed hyperenhancement (HE) on late gadolinium enhancement (LGE) cardiac magnetic resonance imaging (CMR), which greatly magnifies the risk of (sudden) cardiac death, appropriate ICD shock, and HFH. 5,7Apart from myocardial HE, delayed hyperenhancement of the papillary muscle (papHE) is another promising factor that has recently been linked to ventricular arrhythmias and SCD in patients with ischemic cardiomyopathies, independently from the extent of myocardial HE. 8 The exact prevalence and prognostic implications of papHE in DCM patients were unknown however.Therefore, this study aimed to describe the prevalence of papHE in DCM patients and to assess its incremental prognostic impact over myocardial HE.We hypothesized that papHE occurs in DCM patients and that its presence may be associated with increased mortality.If true, the presence of papHE in DCM may serve as a novel selection criterion for ICD allocation.

METHODS
For this retrospective analysis of a prospectively included cohort, consecutive patients with nonischemic DCM were included from the Maastricht Cardiomyopathy registry (NCT04976348), who were enrolled between 2003 and 2018.The exact selection criteria 9 and other results 10 have previously been published.Briefly, we included patients with DCM or hypokinetic non-DCM as defined according to international definitions, 11   Left atrial dimensions and left atrial reservoir strain were computed following a previously published protocol. 10The LV ejection fraction was calculated as: (LV end-diastolic volumeÀLV end-systolic volume)/ LV end-diastolic volume Â 100.Myocardial HE was measured semiquantitatively using the full-width at half maximum technique 13 and expressed as a percentage of end-diastolic LV mass.
The presence of papHE was assessed visually and blinded from patient outcomes, following 3 steps.
First, an experienced investigator identified the supero-lateral and infero-medial papillary muscle bundles on short axis cine images, which may consist of several muscle heads.The number of heads per group was counted as demonstrated in Supplemental     PRIMARY OUTCOMES.Median follow-up time from enrollment in the registry until death or censoring was 6.1 years (IQR: 3.7-9.7 years).During this period, 38 patients with papHE (29%) had a total of 65 events, and 52 patients without papHE (13%) had 79 events, see Supplemental Table 1.The simultaneous occurrence of myocardial and papillary HE consistently led to the highest incidence of all-cause and sudden death, HFH, and LTA, see Table 3.In univariable Cox regression analysis, there was a significant association between simultaneous occurrence of papHE and myocardial HE and all tested outcomes (Table 4).No significant association was observed between isolated papHE and any of the tested outcomes.Similarly, isolated myocardial HE had a borderline association with SCD only (HR: 2.55, 95% CI: 0.98-6.63).See Figure 2 and the Central Illustration for the unadjusted cumulative incidence functions of the main outcomes.In multivariable analysis, the presence of isolated papHE and isolated myocardial HE were not associated with any of the main outcomes.In contrast, the simultaneous presence of myocardial HE and papHE was associated with all-cause mortality (HR: 2.33, 95% CI: 1.26-4.30),SCD (HR: 3.77, 95% CI: 1.59-8.94),LTA (HR: 3.94, 95% CI: 1.34-11.58),and HFH (HR: 2.97, 95% CI: 1.30-6.80),see Table 4.The effect sizes were similar in the reduced model that corrected for LVEF only.No difference in effect size was observed between the Cox multivariable models and the Fine-Gray subdistribution hazard models

Beijnink et al
Additionally, the effect of papHE increased with its extent.For instance, tipHE was not associated with   cantly associated with all events except for LTA, with a higher HR than papHE scores # median (see Supplemental Table 3).

DISCUSSION
We investigated the prevalence of delayed HE of the papillary muscles in patients with DCM and its incremental prognostic impact over myocardial HE.
Two-thirds of the patients had tipHE and 1 in 4 patients had papHE.Although tipHE, isolated myocardial HE, and isolated papHE were not significantly associated with adverse outcomes, simultaneous papHE and myocardial HE increased the risk of allcause mortality, SCD, LTA, and HFH, after correction for demographic and LV functional covariables.

PREVALENCE OF PAPILLARY MUSCLE DELAYED
HYPERENHANCEMENT AND CLINICAL OUTCOMES.
In a referred population that was scanned for cardiomyopathy indications, papHE was found in 29 out of 149 patients (19%) with a nonischemic cardiomyopathy. 15There, the presence of papHE was not associated with all-cause mortality, worsening heart failure, and cardiac-related hospitalization after 3 years.We studied a larger population with extensive follow-up, assessing HFH and different types of mortality, as well as LTA.In line with earlier work, papHE was found in a quarter of DCM patients.On the other hand, in the presence of myocardial HE, papHE was associated with adverse outcomes.These associations were independent from demographic covariables and LV ejection fraction.The presence of isolated tipHE without involvement of the papillary muscle, however, was not associated with any of the studied outcomes.Additionally, combined myocardial and papHE led to a higher risk   of SCD and LTA as compared to myocardial HE alone.
In conclusion, papHE is seen in a quarter of DCM patients and its presence is associated with a broad spectrum of clinical adverse events, mainly when papHE coexists with myocardial HE.
PATHOPHYSIOLOGICAL MECHANISMS.An expansion of the extracellular matrix is a typical feature that unites ischemic 16 and nonischemic cardiomyopathies. 17The extracellular matrix can have different microscopical phenotypes depending on the causal disease.Phenotypes may range from replacement fibrosis and sarcoid depositions to amyloid depositions.Gadolinium-based contrast agents wash out of the expanded extracellular matrix at a slower pace, due to relative hypoperfusion or an increased affinity for said environment, causing delayed HE. 18 First, we demonstrate that papHE results in the increased rates of LTA and SCD on 1 hand and HFH on the other.Firstly, we speculate that papHE may lead to HFH as the papillary muscle contains contractile myocardial units 19  Whether the incorporation of papHE in addition to myocardial HE improves ICD recommendation guidelines needs to be confirmed in future studies.

FUNDING SUPPORT AND AUTHOR DISCLOSURE
The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

(
who are gathered under the term DCM.Both were defined as having an LV ejection fraction <50%.A diagnosis of DCM was made when the LV end-diastolic diameter >33 mm/m 2 in men or >32 mm/m 2 in women.Patients were diagnosed with hypokinetic non-DCM when the LV end-diastolic diameter #33 mm/m 2 in men or #32 mm/m 2 in women.The exclusion criteria for the registry were as follows: 1) the presence of significant coronary artery disease, defined as an epicardial stenosis >50% (as assessed by coronary artery angiography or computed tomography angiography); 2) prior myocardial infarction on LGE CMR; 3) primary valvulopathies; 4) the presence of congenital heart disease; 5) acute myocarditis; 6) arrhythmogenic cardiomyopathy; 7) hypertensive or hypertrophic cardiomyopathy and restrictive or peripartum cardiomyopathy; and 8) the presence of myocardial storage diseases.Of the 551 patients with available scans, LGE CMR images were missing in 4 cases, and LGE CMR images were of an uninterpretable quality in 19 cases.These patients were excluded from the analysis, resulting in a study population of 528 patients.The study was approved by the local ethics committee and performed in accordance with the Declaration of Helsinki.All patients gave written informed consent.CLINICAL FOLLOW-UP AND OUTCOMES.All patients participated in elaborate outpatient work-up, including a physical exam and anamnesis.Clinical events were collected from the medical records and telephone contact with the general practitioner.Mortality data were extracted from the municipal registry.Starting from index CMR, the primary outcomes were recorded.These included: 1) all-cause mortality; 2) SCD, defined as unexpected mortality in a previously stable patient; 3) life-threatening arrhythmias (LTA), defined as nonfatal ventricular fibrillation and/or ventricular tachycardia with hemodynamic instability, with or without appropriate ICD shock; and 4) HFH, defined as admission for >24 hours with a primary diagnosis of heart failure or progressive deterioration of heart failure demanding intensified treatment.12CMR IMAGING.The CMR images were acquired on a clinical 1.5-T MRI scanner (Intera, Philips Medical Systems).The scanning protocol consisted of standard long axis 2-, 3-, and 4-chamber cine imaging.A short axis cine stack was acquired consequently, covering the entire LV.The cine images were acquired during end-expiratory breath holds, using a balanced steady-state free precession sequence of A B B R E V I A T I O repetition time: 3.0-3.5 milliseconds; echo time: 1.

Figure 1 .
Figure 1.Consequently, the papillary muscles were identified on the LGE CMR images at the same slice position.The presence of papHE was defined as HE in a papillary muscle head in 2 contiguous LGE CMR slices and its presence needed to be confirmed on the long-axis LGE CMR slices.If the 2D inversion recovery gradient echo LGE CMR images were of insufficient quality, papHE was evaluated on the single shot images.Difficult cases were discussed with a senior CMR physician with >15 years of experience, until consensus was reached.If papHE was seen in only 1 basal slice adjacent to the chordae tendineae and confirmed in a long-axis LGE CMR view, this was defined as papillary tip HE (tipHE).Figure 1 contains an example of complete papHE and tipHE.Consequently, the nature and extent of papHE were

FIGURE 1
FIGURE 1 Delayed Hyperenhancement of the Papillary Muscle and Papillary Muscle Tip
Papillary Muscle Delayed Hyperenhancement in DCM any of the main outcomes, whereas papHE # median score was associated with all-cause mortality and HFH.A papHE score above the median was signifi-

FIGURE 2
FIGURE 2 Prognostic Implications of papHE and Myocardial HE on All-Cause Mortality, Life-Threatening Arrhythmias, and Hospitalization for Heart Failure

J
A C C : A D V A N C E S , V O L . 3 , N O .8 Papillary Muscle Delayed Hyperenhancement in DCM CENTRAL ILLUSTRATION Combined Papillary and Myocardial Delayed Hyperenhancement Increase the Risk of Sudden Cardiac Death Beijnink CWH., et al.JACC Adv.2024;3(8):101103.(A to C) 2-chamber, 4-chamber, and short axis LGE CMR images of a patient with papHE and myocardial HE. (D) Cumulative incidence function based on the presence of papillary HE, myocardial HE, or both, with regard to the incidence of sudden cardiac death.(E) Multivariable HRs of isolated and combined papHE and myocardial HE, after correction for age, sex, and LVEF.The hazard ratios for the presence of papillary HE, myocardial HE, and papillary and myocardial HE were computed with neither papillary or myocardial HE as the reference group.Correction was applied for age (continuous), sex (males reference), and LV ejection fraction (continuous).HE ¼ delayed hyperenhancement; LGE CMR ¼ contrast-enhanced cardiac magnetic resonance imaging; LVEF ¼ left ventricular ejection fraction; papHE ¼ papillary muscle delayed hyperenhancement.Beijnink et al J A C C : A D V A N C E S , V O L . 3 , N O .8 , 2 0 2 4 Papillary Muscle Delayed Hyperenhancement in DCM A U G U S T 2 0 2 4 : 1 0 1 1 0 3

:
Dr Robin Nijveldt, Department of Cardiology, Radboud University Medical Center, Geert Grooteplein Zuid 10, Nijmegen 6525 GA, the Netherlands.E-mail: robin.nijveldt@radboudumc.nl.PERSPECTIVES COMPETENCY IN MEDICAL KNOWLEDGE: PapHE is a relatively frequent finding in patients with DCM.Its presence is often subtle and easily overlooked.However, papHE is associated with worse outcomes and may become a standard part of a CMR report.TRANSLATIONAL OUTLOOK: DCM patients with papHE and myocardial HE fall in a high-risk category for sudden cardiac death, life-threatening arrhythmias, and HFH.Future prospective studies are needed to investigate if the incorporation of papHE in decision-making strategies could improve ICD allocation.
Papillary Muscle Delayed Hyperenhancement in DCM R E F E R E N C E S

TABLE 4
The Effect of Papillary and Myocardial Delayed Hyperenhancement on Clinical Outcomes Values are HR (95% CI).Significant values are highlighted in bold.The hazard ratios for the presence of papillary HE, myocardial HE, and papillary and myocardial HE were computed with neither papillary or myocardial HE as the reference group.Correction was applied for age (continuous), sex (males reference), and LV ejection fraction (continuous).a No life-threatening arrhythmias were seen in patients with isolated papHE.HE ¼ Delayed hyperenhancement; LV ¼ Left ventricle; papHE ¼ papillary muscle delayed hyperenhancement.
and if these are lost, LV contrac- 1. Elliott P, Andersson B, Arbustini E, et al.Classification of the cardiomyopathies: a position statement from the european society of cardiology working group on myocardial and pericardial diseases.Eur Heart J. 2008;29:270-276.2. Marume K, Noguchi T, Tateishi E, et al.Mortality and sudden cardiac death risk stratification using the noninvasive combination of wide QRS duration and late gadolinium enhancement in idiopathic dilated cardiomyopathy.Circ Arrhythm Electrophysiol.2018;11:e006233.3. Zeppenfeld K, Tfelt-Hansen J, de Riva M, et al. 2022 ESC guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: developed by the Task Force for the Management of Patients with Ventricular Arrhythmias and the prevention of sudden cardiac death of the European Society of Cardiology (ESC) Endorsed by the Association for European Paediatric and Congenital Cardiology (AEPC).Eur Heart J. 2022;43:3997-4126.4. Moss AJ, Hall WJ, Cannom DS, et al.Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia.Multicenter Automatic Defibrillator Implantation Trial Investigators.N Engl J Med. 1996;335:1933-1940.